Canvassing for Opinion - aka "Blairs Brain on Cannabis"

IMHO prohibition sentiment requires inherent addiction to status quo, an incapacity to visualise beyond the here and now and a desperate desire to know others might feel the same...
Reform is not revolutionary, rather it is evolutionary. Having survived banging your head against a brick wall the evolutionist relishes having stopped. / Blair

Monday, October 30, 2006

Punishment Without Jail

"We need to make sure there are adequate services available for addicts and for those things which are often driving people into criminal activity in the first place, " Major Roberts said.

The Rethinking Crime and Punishment campaign would provide factual material to balance the emotions stirred up by individual violent crimes, he said.

This article will examine harm reduction from a novel perspective. Its central thesis is that harm reduction is not only a social concept, but also a biological one. More specifically, evolution does not make moral distinctions in the selection process, but utilizes a cannabis-based approach to harm reduction in order to promote survival of the fittest. Evidence will be provided from peer-reviewed scientific literature that supports the hypothesis that humans, and all animals, make and use internally produced cannabis-like products (endocannabinoids) as part of the evolutionary harm reduction program. The concept of harm reduction is at the heart of conflicting international drug policies. It was originally pioneered by the Dutch. Today most European countries and Canada have embraced the idea that society benefits most when drug policy is designed to help people with drug problems to live better lives rather than to punish them. In contrast, the United States demands a rigid zero tolerance policy with overwhelming emphasis on incarceration of offenders (the Drug War). Although, seemingly reasonable arguments can be made to support both sides of the dispute, the recent global trend towards harm reduction has resulted from the acknowledgement that drug use has been a part of all societies throughout history and the realization that repressive policies are expensive, ineffective, and in fact harmful. A dramatic example of the benefits that can result from a harm reduction approach to drugs is seen with needle exchange programs. While prohibitionists argue that providing clean injection equipment promotes drug use, the facts do not support this contention. For example, the Australian needle exchange program is credited with keeping the HIV/AIDS infection rate very much lower than what is typically found globally ( http://www.chr.asn.au/about/harmreduction ). Commonly cited examples of the failed repressive policies championed by the United States are the now repealed alcohol prohibition and the current drug war. Crime, financial support for terrorism, disrespect for the law, destruction of families, communities, and ecosystems can all be attributed to drug prohibition. Yet, the staggering cost of the drug war, driven by United States policy and taxpayers' money, amounts to many billions of dollars a year. A significant portion of the drug war effort is focused on cannabis prohibition. Is it justified?Cannabis is the third most commonly used drug in the world, following tobacco and alcohol. In the United States, much of the drug war is focused on marijuana (over 700,000 people arrested last year alone). Is there justification for this policy? The gateway theory, that marijuana use leads to other drugs, drives this policy despite evidence that suggests alcohol and tobacco use may foster the gateway affect 1 2. In contrast, countries that support harm reduction focus their enforcement and social support efforts on "hard drugs." Consequently, many countries have effectively decriminalized marijuana. Holland, having the most liberalized drug laws, does not have more cannabis users (over age twelve) than do more repressive countries, and the per capita number of heroin users is also lower ( http://www.minjust.nl:8080/a_beleid/thema/drugs/drugs.htm ). The Dutch Ministry of Justice estimates that 0.16% of cannabis users are heroin users. This figure does not support cannabis being a gateway drug. Data from 2000 National Household Survey on Drug Abuse (US DEPARTMENT OF HEALTH AND HUMAN SERVICES, Substance Abuse and Mental Health Services Administration) also shows that the vast majority of people who try cannabis do not go on to use hard drugs.A little explored question is, what does harm reduction specifically mean with respect to cannabis consumption. This article will address cannabis harm reduction from a biological perspective. Two directions will be examined: what are the biological effects of cannabis use and what are the social effects that emerge from the biological foundation. Like many substances that are put into the human body, there can be positive or negative consequences that result from cannabis consumption, depending on amount, frequency and quality. Prohibitionists concentrate their efforts on the negative effects of cannabis use, while anti-prohibitionists tend to focus on the positive effects. If we assume that both sides have valid arguments, the issue to be resolved is one of balance between the negative and positive effects. Would a policy of tolerance or prohibition be more likely to reduce harm overall, and better serve society as a whole, as well as problematic drug users? Biological science can be more objectively evaluated than social science. The central theme that will be promoted in this article is that appropriate cannabis use reduces biological harm caused by biochemical imbalances, particularly those that increase in frequency with age. Additionally, speculation will be offered suggesting possible social benefits that can arise from the intelligent use of cannabis. Proper cannabis use, as distinguished from misuse, may have significant positive health effects associated with the way cannabis mimics natural cannabinoids. In essence, it is proposed that the endocannabinoid system, selected for by 600 million years of evolution, is a central mediator of biological harm reduction through its homeostatic activities. The social implications of cannabis use will be viewed as emerging from the biological platform. Here in lies the paradox of cannabis and harm reduction. Is appropriate use of cannabis better than no use? Cannabis use can be divided into two categories, recreational and medical, although some, including those who favor or oppose cannabis use, presume they are the same. On the one side, it is often claimed that any cannabis use is justified by some underlying medical need. On the other side, cannabis use is presumed to have no medical value, with the implication that those who use it are simply "getting stoned." While the former claim may be too extreme, the latter defies current scientific understanding of the biological functions of the endocannabinoids. While many people are reluctant to approve recreational cannabis use, it appears that most people support medical use. Hypocritically, the United States Federal Government denies that there is any valid medical use for cannabis, while the National Institute of Drug Abuse (NIDA) provides marihuana on a monthly basis to a few medical users through the Compassionate Investigatory New Drug (IND) program of the Federal Drug Administration (FDA). Nevertheless, a number of states, through either legislative action or voter initiative, have approved the use of medical marijuana.3In order to better assess arguments for and against the medical use of marijuana, the scientific evidence for the health benefits of cannabis will be reviewed below. It should be noted that the federally supplied cannabis users have been receiving and using cannabis for 11 to 27 years with clinically demonstrated effectiveness in the treatment of glaucoma, chronic musculoskeletal pain, spasm and nausea, and spasticity of multiple sclerosis.4 Furthermore, there is no evidence that these patients have suffered any negative side-effects of their cannabis use.Cannabis preparations have been used medically for thousands of years for illnesses such as epilepsy, migraine headaches, childbirth, and menstrual symptoms. However, it is only relatively recently that the active components have been identified and their mechanisms of action have begun to be understood. While delta-9-tetrahydrocannabinol (THC) was first synthesized by Mechoulam in 1967,5 it was not until 1990 that the cannabinoid receptor was localized in the brain,6 and cloned.7 Since then, discoveries in the field have proceeded at an ever-increasing pace. The discovery of cannabinoid receptors on cells naturally prompted the search for internal compounds (endogenous ligands) that would activate the receptors since it seemed unlikely that cannabis receptors had evolved so people could partake of cannabis. In 1992, anandamide was discovered.8 This lipid metabolite was the first ligand of an ever-expanding class of molecules known as endocannabinoids (internal marijuana-like compounds) to be discovered. Endocannabinoid synthesis, degradation, transport, and receptors together form the endocannabinoid system.The broad therapeutic potential that can result from correctly manipulating the endocannabinoid system is just beginning to be realized.9,10 In fact, major pharmaceutical companies, and university researchers all around the world are now engaged the cannabinoid related research.11 Their efforts focus on learning how the endocannabinoid system functions, and on how to manipulate it in order to increase or decrease its activity, depending on the illness or condition under consideration. GW Pharmaceuticals in Britain has been developing and testing a plant extract-based product line that is in clinical trials in Britain and Canada.12 The results thus far have been positive to the extent that Bayer AG has entered into a 25 million dollar distribution agreement for GW's product, Sativex.The cannabinoid system appears to be quite ancient,13,14 with some of its components dating back about 600 million years to when the first multicellular organisms first appeared. The beginnings of the modern cannabinoid system are found in mollusks15 and hydra.16 As evolution proceeded, the role that cannabinoid system played in animal life continuously increased. It is now known that this system maintains homeostasis within and across the organizational scales of all animals. Within a cell, cannabinoids control basic metabolic processes such as glucose metabolism.17 They regulate inter-cellular communication, especially in the immune18 and nervous systems.19 In general, cannabinoids modulate and coordinate tissues, organ and body systems (including the cardiovascular,20 digestive,16 endocrine,21 excretory,22,23 immune,18 nervous,19 reproductive,24 and respiratory25 systems). The effects of cannabinoids on consciousness are not well understood, but are well known, and underlie recreational cannabis use. These effects also have therapeutic possibilities.26The homeostatic action of cannabinoids on so many physiological structures and processes is the basis for the hypothesis that the endocannabinoid system is nothing less than a naturally evolved harm reduction system. Endocannabinoids protect by fine-tuning and regulating dynamic biochemical steady-states within the ranges required for healthy biological function. The endocannabinoid system itself appears to be up- or down-regulated as a function of need. As will be elaborated in more detail later in this article, endocannabinoids levels naturally increase in the case of head injury and stroke,27 and the number of cannabinoid receptors increases in response to nerve injury and the associated pain.28 In contrast, the number of cannabinoid receptors is reduced when tolerance to cannabinoids is induced.29To illustrate the multidimensional biochemical balancing act performed by cannabinoids, a variety of endo- and exo-cannabinoid activities will be reviewed below. In order to appreciate these activities a brief introduction to cell biology may help to provide the context for this review. All life is dependant upon the maintenance of its dynamic organization through sufficient input of nutrients and removal of wastes. The more complicated an organism is, the more complex the coordination required to accomplish the essential tasks required to maintain this vital flow of inputs and outputs. Coordination requires communication. Cells communicate by thousands of different, but specific, receptors on cell surfaces that respond to thousands of different, but also specific, molecules (ligands) that bind to the receptors. A receptor that is bound to its activating ligand causes biochemical changes to occur in the cell. In response to such regulatory signals on the membrane, biochemical regulation within the cell occurs at the level of gene _expression as well as at the level of enzyme action and other processes outside the nucleus. Ultimately these changes, through complex biochemical pathways, allow cells to divide, carry out specialized tasks, lie dormant, or die. Any of these cellular activities, when not properly coordinated, can result in illness. Two major categories of disease states are those that result from acute illness commonly caused by infections and those that are age-related. Historically, in the United States, the cause of death has transitioned from pathogen-induced to age-related. Current scientific literature regarding cannabis indicates that its use is often bad for the former but good for the latter.Since cannabis' action on the brain is most widely known due to its recreational use, the nervous system will serve as the starting point for examining cannabinoid activity as an example of of a natural biological harm reduction system. Numerous disease states associated with the nervous system will be seen as potential targets for cannabinoid based therapy.30 The nervous system is composed of nerve and supporting cells. In addition to the role cannabinoids play in a normal healthy nervous system,31 the regulatory effects of cannabinoids in cases of stroke,27 Parkinson's disease,32 Huntington's disease,33 Alzheimer's disease,34 glioma (a type of brain tumor),35 multiple sclerosis,36 seizures37, and pain38,39 will be examined. In a healthy individual, cannabinoids play a direct role in neurotransmission of many nerve cell types. They often exhibit the unusual property of retrograde transmission, in which the neurotransmitter diffuses backwards across the neural cleft to inhibit the pre-synaptic action potential.40 This function essentially regulates the sensitivity of a nerve cell (in its release of neurotransmitters in response to inputs of neurotransmitters) by acting as a feedback mechanism that prevents excessive activity. Some nerve cells die when they are excessively stimulated by excitatory neurotransmittors (excitotoxins) such as glutamate. Cannabinoids can reduce the level of stimulation and protect against this form of cell death.41,42 In addition to their down-regulatory effect on neurotransmission, recent work has elaborated other roles that cannabinoids play in reducing this type of cell death (harm reduction) by defining the role of interleukin-1 (IL-1) and the IL-1 receptor antagonist (IL-1ra).43 Cannabinoids were shown to modulate the release of IL-1ra by which they protect against IL-1 assisted cell death.44The role of cannabinoids in neurological health and disease goes beyond the prevention of cell death. Cannabinoid receptors appear to be functionally coupled to the fibroblast growth factor receptor (FGF). The FGF receptor, when stimulated, activates diacylglerol (DAG) lipase causing the hydrolysis of DAG to produce 2-arachidonyl glycerol (2AG).45 2AG is an endocannabinoid shown to be important for axon growth and guidance.46 The ability to control these fundamental neurological activities, in conjunction with the anti-inflammatory properties of cannabinoids, is likely to have important regenerative health benefits for people suffering from neurological damage as occurs with stroke or injury.27Both animal and human studies provide strong evidence of the therapeutic potential of cannabinoids to provide relief from a number of neurological disease states.47 The use of cannabinoids to treat people suffering from multiple sclerosis (MS) is an excellent example of the importance of "medical marijuana" as an agent of harm reduction.48 MS is a neurodegenerative disease in which the immune system attacks components of the nervous system. The axons of many CNS neurons are surrounded by a myelin sheath that acts much like an insulator around a wire. MS is associated with a degradation of the myelin sheath that leads to loss of axon function and cell death, thus producing the disease symptoms. Cannabis-based therapies for the treatment of MS can provide symptomatic and true therapeutic relief. On the one hand, cannabinoids help to reduce spasticity in an animal model of MS (chronic relapsing experimental autoimmune encephalomyelitis (CREAE)).49 However, the involvement of the cannabinoid system in the etiology of MS goes much deeper. MS is in reality an autoimmune disease. Therefore, in order to appreciate why cannabinoids can have in important role, beyond what has already been mentioned, in treating MS on a mechanistic level 50, a brief introduction to immunology is required. The role of the immune system is simplistically thought of us protecting us from foreign attack. More inclusively, however, the immune system has the biological function of modulating the life, death and differentiation of cells. The immune system accomplishes these tasks, in part, by balancing two mutually opposed pathways known, respectively, as the "Th1" and "Th2" response. The Th1 immune response is critical for fighting infections caused by specific infectious agents,51 This function is inhibited by cannabinoids. Thus cannabinoids are important homeostatic modulators of the immune system. While often classified as immune inhibitors, cannabinoids actually promote the Th2 response as well as inhibiting the Th1 response and are therefore more appropriately termed immune system modulators. A specific cannabinoid receptor (Cb2)52 is found on most cells of the immune system. The Th1 pathway is pro-inflammatory and vital for fending off pathogens, especially intracellular pathogens, such as those that cause Legionella's disease, Leishmania and tuberculosis. Accordingly, harm reduction would be served if the use of cannabis were avoided when the Th1 arm of the immune system is needed. Although contagion as well immune suppression may have been involved, a recent study supports this perspective in tracing a cluster of new tuberculosis cases to a shared water pipe.53 Free radical production, inflammation and cell mediated immunity are characteristic of the Th1 response. The targeting of infectious organisms, or infected cells, by a Th1 immune response results in surrounding cells being exposed to free radicals. Much as if radiation had been applied, there is collateral damage. In contrast, the Th2 immune response promotes the "humoral" arm of the immune system. It is characterized by antibody production, and is typically anti-inflammatory. Ideally, the Th1 and Th2 pathways are functionally balanced to optimally meet the survival needs of an organism in its environment. In reality, however, many autoimmune diseases are characterized by an excessive Th1-driven immune response at the site of the disease that appears to be the cause of the tissue damage involved. Multiple sclerosis, arthritis, Crohn's disease, and diabetes are all diseases that fall into this category. The therapeutic impact of cannabinoids on these diseases can be dramatic. For example, when rodents were given experimental autoimmune encephalomyelitis (EAE) as an MS animal model and were treated with cannabinoids, the results were profound.54 In a study that involved both guinea pigs and rats, 98% of the EAE animals that were not treated with THC died. In contrast, greater than 95% of THC-treated animals survived. They had no symptoms or mild symptoms with a delayed onset. The brief interludes into cell biology, neurology and immunology provides a biological platform for considering how cannabinoids might impact a variety of other disease states. It is important to keep in mind that in its role as a general homeostatic modulator, too much or too little cannabinoid activity can be harmful. Cannabinoid levels or concentration ranges vary as a function of an organism's genetics, the cell types under consideration, their health and environment. Care must be taken when evaluating the scientific literature on cannabinoids and their effects. Cannabinoids often exhibit biphasic responses.55 Low doses of cannabinoids may stimulate the Th2 immunological response, whereas high doses may inhibit the Th2 response and shift the balance in favor of a Th1 response. From a harm reduction perspective, these observations demonstrate the critical importance of of dose-dependent, disease-dependent, state-dependent, and individually tailored approaches to cannabis therapeutics.56The use of cannabinoids in the treatment Parkinson's disease is an example of a condition where excessive or deficient cannabinoid activity may be problematic. Parkinson disease results from the loss of levo-dopamine (L-dopa) producing neurons. In an animal model of Parkinson's disease, L-dopa producing cells are killed with 6-hydroxydopamine. Rats so treated exhibit spontaneous glutamatergic activity that can be suppressed by exo- as well as endocannabinoids.57 The standard treatment for Parkinson's disease involves L-dopa replacement therapy. Unfortunately, this treatment often results in dyskinesia (abnormal voluntary movements). Recent clinical trials have shown that cannabinoid treatment reduces the reuptake of gamma-aminobutyric acid (GABA) and relieves the L-dopa-induced dyskinesia. 32 as well as L-dopa induced rotations in 6-hydroxydopamine-lesioned rats.58 In contrast to the potential benefits of cannabinoid agonists just sited, using a different animal model, the cannabis antagonist SR141716A reduced reserpine-induced suppression of locomotion.59 Thus, in this model, locomotion was restored by inhibiting the endocannabinoid pathway.Possibly the greatest harm-reducing potential afforded by cannabinoids comes from their use by cancer patients. Cannabinoids possess numerous pharmacological properties that should be beneficial to cancer patients. Many people are aware of the anti-emetic and appetite stimulating effects of cannabinoids.60 A systemic study designed to quantify the efficacy of cannabinoids as an anti-emetic agent examine data from 30 randomized controlled studies that were published between 1975 and 1997 and included 1366 patients who were administered non-smoked cannabis.61 For patients requiring a medium level of control, cannabinoids were the preferred treatment (between 38% and 90%). This preference was lost for patients requiring a low or a high level of control. Sedation and euphoria were noted as beneficial side effects, whereas dizziness, dysphoria, hallucinations and arterial hypotension were identified as harmful side effects. The cancer cell-killing62 and pain relieving properties of cannabinoids are less well known to the general public. Cannabinoids may prove to be useful chemotherapeutic agents.63 Numerous cancers types are killed in cell culture and in animals by cannabinoids. For example, cannabinoids kill the cancer cells of various lymphoblastic malignancies such as leukemia and lymphoma,64 skin cancer,65, glioma,66 breast and prostate cancer, 67 pheochromocytoma,68 thyroid cancer 69 and colorectal cancer. 70 Since 2002 THC is being used in clinical trials for the treatment of glioma. However, not all cancers are the same, and cannabinoid-induced biochemical modifications, while effective in killing the cells of some cancers, as indicated above, can have the opposite affect on the cells of other types of cancer. For example, recent work has shown that the synthetic cannabinoid, methanandamide, can promote the growth of lung cancer cells by a receptor independent pathway that involves the up-regulation of COX2.71 Although much has been learned about the therapeutic value of cannabinoid agonists and antagonists in different situations, scientific understanding of how to appropriately modulate the endocannabinoid pathways remains quite preliminary, with much remaining to be learned.One area of current research and that has attracted public interest is the pain relieving potential of cannabinoids, for both cancer72 and non-cancer patients.73 Cannabis extract-based medicine has demonstrated positive effects for pain relief.74 Recently, an intrinsic role for cannabinoids in pain circuitry was discovered. The endocannabinoid AEA was identified as the natural ligand for the vanilloid receptors.75 Vanilloid receptors, which are ligand-gated cation channels, are primary targets for the treatment of pain.76 The cannabinoids seem to function in a pathway parallel to the opiod pathway77 and are thought to exert anti-nociceptic activity at the level of the spinal cord and the brain,78 although they can also act peripherally by inhibiting mast cell degranulation.79 In recognition of the pain relieving properties of cannabinoids, England11 and Canada39 are using cannabis preparations to provide relief to citizens suffering from a variety disorders. Human trials have established that co-administration of cannabinoids can dramatically lower opiod use and can provide pain relief for neurogenic symptoms where other treatments have failed.80 Recently, the topical application of the synthetic cannabinoid WIN 55,212-2 significantly enhanced the antinociceptive activity of morphine, opening the door for possible cannabis induced pain relief with reduced cognitive side effects.81 The intrinsic role of endocannabinoids in modulating pain is further supported by the up-regulation of the CB1 receptor in rats following nerve damage.28 Once again, nature has selected the cannabinoids to reduce harm.Fundamental to any consideration of cannabis-based harm-reduction, as a biological phenomenon or as a policy, is how to best administer the drug. Smoking cannabis preparations, in contrast to oral administration,82 has the benefit of rapid action that allows self-titration of the drug's activity.83,84 Unfortunately, cannabis smoke contains numerous carcinogenic compounds.85 In fact, cannabis smoke may contain more tars than tobacco smoke.86 However, despite the fact that cannabis smoke does produce cellular changes that are viewed as precancerous, a major epidemiological study does not find that cannabis smoking is associated with tobacco related cancers.87 A number of recent studies provide a scientific foundation for the clear relationship between tobacco smoking and lung cancer, a relationship that does not hold true for cannabis smoke (manuscript in preparation). For example nicotine, acting via nicotine receptors, is critical in the development of tobacco related cancer by inhibiting the death of genetically damaged cells.88 In addition, tobacco promotes the development of blood vessels needed to support tumor growth89 whereas cannabis inhibits tumor vascularization in nonmelanoma skin cancer65 and glioma.90 Although conclusions derived from an often-cited study examining the carcinogenic effects of cannabis, tobacco, and cannabis and tobacco combined claims to show a link between cannabis smoking and head and neck cancer,91 However, these results do not hold up under scrutiny. The study does support a link between tobacco use that is exacerbated by concurrent cannabis use and the development of head and neck cancer. However, the "cannabis use only" group was only composed of two subjects, undermining the statistical relevance of conclusions regarding this group.Regardless of whether or not smoking cannabis can cause lung cancer, smoking anything containing partially oxidized hydrocarbons, carcinogens and irritants a priori, is not healthy and will have negative health consequences. Fortunately, harm-reducing alternatives exist. While often taughted as a problem, the availability of high THC cannabis with high levels of THC permits less cannabis to be smoked for therapeutic effects. Additionally, methods of vaporizing the active ingredients of cannabis have been shown to successfully remove most compounds of concern while efficiently delivering the desired ones. See D. Gieringer, "Cannabis Vaporization: A Promising Strategy for Smoke Harm Reduction," Journal of Cannabis Therapeutics Vol. 1#3-4: 153-70 (2001). These results contrast with a recent Australian study that found that the use of a water pipe, or bong, failed to reduce tars or carbon monoxide delivered to the smoker (Linda Gowing et al. "Respiratory Harms of Smoked Cannabis," Research Monograph No. 8. Adelaide: Drug and Alcohol Services Council of South Australia (2000).) GW Pharmaceuticals is developing an oral spray that should prove to be an additional safe and effective alternative delivery system12 and of value to medical cannabis users. The company has also identified strains with defined ratios of various cannabinoids for which specific medicinal value will be determined.Another important cannabis-harm-reduction topic that must be considered is that of how the use of cannabis impacts on the pharmokinetics of other drugs.92 A number of drugs are metabolized by the P450 family of isoenzymes, including numerous cannabinoids.93 Even though cannabinoids stimulate the transcription of P450 (2A and 3C), they also directly inhibit the activity of this enzyme.94 There are likely to be pro's and con's associated with P450 inhibition. P450 activity activates procarcinogens in tobacco smoke to create active cancer-causing mutations.95 Thus the inhibition of these enzymes by cannabinoids may minimize some of the negative consequences of smoke inhalation. On the other hand, many pharmaceuticals are also metabolized by these enzymes. The reduction of the rate of drug metabolism by cannabinoids with pharmokinetic consequences has been shown for cocaine,96 barbiturates97 (Biochem Pharmacol, 41, 109-13). opiates,98 alcohol, the antipsychotic haloperidol,99 and others.100Thus far, both endo- and exo-cannabinoids are seen to reduce harm in numerous circumstances. Cannabinoid-based therapies have been especially helpful for the treatment of a variety of neurological and immunological disorders. Yet we have only scratched the surface of the scientific literature on the cannabinoids and their biological effects. Nevertheless, it should be apparent that cannabinoids will have enormous medical potential as we learn to manipulate the natures cannabinoid harm-reduction system that has evolved in the animal kingdom. Before moving on to consideration of the possible social impact of cannabinoid use, we consider the following quote from the Drug Enforcement Agency, which illustrates the failure of prohibition policy makers to take into account current peer reviewed scientific literature in their decision making process. Without realistically acknowledging the demonstrated and proposed medical benefits of cannabis, how can a responsible cannabis policy be implemented?There are over 10,000 scientific studies that prove marijuana is a harmful addictive drug. There is not one reliable study that demonstrates marijuana has any medical value. (http://www.usdoj.gov:80/dea/pubs/sayit/myths.htm)A fundamental question that remains unanswered is how basic, complex biochemical phenomena, as touched on briefly in this article, collectively emerge as substantial contributors to health and behavior. In far-from-equilibrium thermodynamic systems, such as living organisms, there are discontinuities between underlying molecular dynamics and associated emergent macroscopic phenomena.101 In such systems, small changes (called "perurbations") can amplify with consequences for the organization of the whole system. The cannabinoids help to regulate an amazingly broad range of biochemical events. All of these effects have genetic foundations. As such, natural genetic/biochemical variation in a population can be expected to have significant effects on health and behavior. It should be expected that in a population distribution of cannabinoid levels and senstivities, as a function of an individual's health/disease status, some individuals would naturally need to increase their cannabinoid activity while others would need theirs lowered. More generally, although the focus of this paper has been to suggest the many circumstances in which higher cannabinoid activity would be beneficial, these circumstances will necessarily differ among individuals with different congenital cannabinoid levels and sensitivities. Therefore, reduced cannabinoid activity would be beneficial under some conditions. The broad homeostatic activities of cannabinoids that have been developed in this article have been rooted in hard science. The extension of these ideas to the psychological and behavioral levels is intrinsically more speculative, but remains consistent with the literature. For years, researchers have looked into the possible addictive qualities of cannabis. The lack of significant reward behavior was indicated by the lack self-administration in primates. Experiments examining preference in rats demonstrated that low doses of THC could induce place preference but that higher doses produced drug aversion,102 again demonstrating the homeostatic nature of cannabinoids. Self-administration is typical of most psychoactive drugs of abuse. Hence, one could conclude that marijuana has a low potential for abuse.Some may question the conclusion that cannabis has a low abuse potential since an animal model using squirrel monkeys was recently developed in which self-administration behavior was maintained using THC.103 Interestingly, and consistent with the notion that the cannabinoid system is a biological homeostatic harm reduction mechanism, the self-administration of THC occurs in a window of from 2 to 8 ug/kg that peaks at 4 ug/kg.104 Thus, in this animal model a controlled dose is chosen. To further put these experiments in perspective, the dose used must be examined more closely. A 1 gram joint of 10% THC content would contain 100 mg of THC. The self-administered dose schedule chosen by the animal of 4 ug/kg would correspond to 360 ug of THC (approximately 1/278 of the joint) for a 200 pound human. Similarly, in rats, the intravenous self-administration of the synthetic cannabinoid Win 55,212-2 also occurred in a biphasic manner, with a maximum response occurring at 12 ug/kg.105 The self-regulated, controlled use of low drug doses is not characteristic of addictive drugs of abuse.Additional cannabinoid involvement in reward behavior is suggested by the increased activity of dopaminergic neurons stimulated with psychoactive cannabinoids.106 This pathway is shared by other major drugs of abuse including morphine, ethanol and nicotine.107 However, the production of glucocorticoid hormones, normally produced in response to stress,108 are suppressed by cannabinoids.109 Are cannabinoids addictive, is pleasure addictive, or is a low stress state addictive? Stress and reward are complicated components of addictive behavior. How does repeated use of THC influence these states? A recent study examines this question by measuring glucose utilization is different areas of the rat brain following repeated treatment with THC.110 After 7 and 21 days of THC treatment, THC no longer resulted in reduced glucose utilization in many areas of the brain typically affected by a single THC dose (most cortical, thalamic and basal ganglia regions). In contrast, glucose utilization in other areas of the brain remained unaltered (nucleus accumbens, mediodorsal thalamus, basolateral amygdala, portions of the hippocampus and median raphe). Thus while the affects of THC on body temperature and locomotor activity become resistant to repeated THC administration, those areas involved in many higher brain functions remain responsive to THC. This differential adaptation to THC administration is consistent with a low addictive potential. The best evidence that demonstrates the absense of an addictive response to cannabis use is the fact that most people who use it at do not continue to use it, and stop using it without any effort. The stress relieving properties of cannabinoids are an important aspect of their pharmacological activity. An interesting mechanism by which cannabinoids may promote stress relief is through their affects on memory. Cannabinoids control the extinction of aversive memories.111 What a blessing for those suffering from painful, debilitating and life threatening illnesses: cannabinoids may help them to forget their misfortune.Independently of the direct addictive or non-addictive properties of cannabis, the cannabis-opiod connection will be examined in more detail. Both drug families function (not necessarily exclusively) through biochemical pathways that are regulated by specific receptor-ligand interactions. However, there appears to be, as yet not fully defined, crosstalk between these pathways.112 For example, CB1 receptor knockout mice are non-responsive to CB1 cannabinoid activities and show reduced addictive effects of opiates.113 Similarly, Lewis rats showed enhanced sensitivity to morphine self-administration after treatment with the synthetic cannabinoid CP55040.114 Examining the cannabis/opioid connection from the other direction, chronic morphine administration results in some down-regulation of cannabinoid receptors along with a significant reduction in 2-AG.115 These results show both positive and negative feedback relationships between the endocannabinoid and opiate systems. They also suggest that cannabinoids might serve to reduce the symptoms of opiate withdrawal.116 The possibility that cannabinoids could serve as an addiction interrupter was demonstrated in rats where the synthetic cannabinoid agonist Win 55-212,2 reduced intravenous self-administration of cocaine.117Behavioral processes and their complexities set man apart from other animals. Can we simply extrapolate from animal to human behavior? It is one thing to comparatively examine the molecular and cell biology of animals and extrapolate to humans. However, the behavioral repertoire of humans appears to be dramatically enhanced over other animals and is therefore more difficult to connect between the species. Evolutionary relationships show that the cannabinoid receptors are located in the more advanced areas of our brains. Again, any population is always a spread around the average value of any parameter. A subset of the human population will inevitably retain a more primitive behavioral repertoire. Are such individuals more susceptible to addictive behavior or psychological problems that could result from cannabis consumption? Has the cannabinoid system been optimized for the regulation of more primitive behavior or, alternatively, is it better optimized for the behavioral flexibility required of modern humans? Indeed, is there any evidence that it, like our cortical capacity, may enable even greater behavioral flexibility in the more complex societies and altered environments of the future?Answers to these questions are suggested by the data of human cannabis consumption. Most people who use cannabis in their youth stop using it as their lives progress. Most do so as a natural part of their development. They do so without outside intervention or help. They do so without ever having become heroin users, schizophrenic, or motivationally compromised. These are the real world facts. They indicate that for the majority of people who try marijuana, it is not addictive, does not lead to heroin usage, or a trigger for the onset of psychological problems. This does not rule out the likelihood that some small percentage of cannabis users may as a result, be victimized by such problems. In fact, the biology presented in this paper suggests that such individual differences should be expected. Individuals negatively affected by cannabis use are the people that an intelligent drug policy would help to identify and assist. In contrast, our policy criminalizes the majority of users and further harms them, perhaps psychologically as well as medically, through it repercussions.The use of cannabis-and any mind-altering drug-by young developing minds rightfully remains an area of focus and concern. However, incomplete knowledge coupled with fear is not likely to result in functional solutions to the problem of teen drug abuse. The "Reefer Madness" approach has not been successful. It is very difficult to define cause and affect relationships when dealing with behavior. An example of this difficulty is suggested by the possible relationship between cannabis use and schizophrenia . Schizophrenia is characterized by distortions of reality, disturbances of language and thought processes, and social withdrawal. Certainly, aspects of cannabis intoxication parallel these symptoms. It is feared that cannabis can precipitate this state,118 especially in susceptible individuals.119 It has been suggested that schizophrenics (or potential schizophrenics) fall into two categories with respect to cannabis use.120 One group may find symptomatic relief in the use of cannabis, while the other may actually take the risk of precipitating the onset of the disease. The complexities of this issue are illuminated by the unpredictable behavior of interacting complex systems such as the nervous and immune systems, as will be considered below.In an important recent study, De Marchi et al.121 examined the endocannabinoid levels in healthy volunteers and compared them to that of schizophrenic patients, both before and after successful antipsychotic treatment. Patients suffering with acute disease had significantly higher anandamide levels in their blood than did the normal individuals or patients in clinical remission. Might these elevated cannabinoid levels be contributing to the disease symptoms, and what might be causing them? Cannabinoids act homeostatically across biological subsystems. A possible immune involvement in schizophrenia has long been suspected, and immunological parameters have been implicated in the disease. For example, there is an inverse correlation between schizophrenia and rheumatoid arthritis; an individual generally does not get both illnesses.122 Interestingly, schizophrenia has been correlated with HLA type, Toxoplasma gonodii infection and exposure to cats.122 Toxoplasma gonodii infects brain neurons, and is best controlled with a strong pro-inflammatory immune response. Endocannabinoids modulate the pro-inflammatory TH1 response by up-regulating the anti-inflammatory Th2 response. Hence, it is likely that some individuals idiosyncratically respond to Toxoplasma gonodii infections by producing excess endocannabinoids and suffering the associated abnormal mental state. Antipsycotic drugs have actually improved the outcome of infection with this parasite.123In conclusion, evolution has selected the endocannabinoids not only to homeostatically regulate numerous biological phenomena that can be found in every organized system in the body, but to counteract biochemical imbalances that are characteristic of numerous damaged or diseased states, in particular those associated with aging. Starting from birth, cannabinoids are present in mother's milk,124 where they initiate the eating process. If the activity of endocannabinoids in the mouse milk is inhibited with a cannabinoid antagonist, the newborn mice die of starvation. As life proceeds, endocannabinoids continuously regulate appetite, body temperature, reproductive activity and our capacity to learn. When a body is physically damaged, the endocannabinoids are called on to reduce inflammation, protect neurons,125 regulate cardiac rhythms126 and protect the heart from oxygen deprivation.20 In humans suffering from colorectal cancer, endocannabinoid levels are elevated in an effort to control the cancer.70 They help relieve emotional suffering by turning down pain and facilitating movement beyond the fears of unpleasant memories.111 While this review is far from complete, it attempts to provide a conceptual overview that supports the endocannabinoid system as being nature's method of harm reduction. There is a pattern to all the cannabinoid-mediated activities described. Many of the biochemical imbalances that cannabinoids protect against are associated with aging. Aging itself is a system wide movement towards chemical equilibrium (away from the highly regulated far-from-equilibrium state) and as such is an imbalance that all living organisms suffer from. In contrast, the harmful consequences of cannabis use, however exaggerated they often appear to be, are likely to represent significant potential risk for a small minority of the population for whom reduced cannabinoid levels might promote mental stability, fertility or a more regulated consumption of food. Current cannabis policies have sacrificed the potential benefits of cannabis for the majority in an effort, whether uninformed or moralistic, to protect the few. Today's harm amplification policy defies science and nature. It must be replaced with a harm reduction policy, one that makes every effort to minimize the risks to a minority of the population while it promotes appropriate medical treatment, needed research, and informed personal use.Acknowledgments Dr. Aimee Stephenson and Dr. Larry Goldberg are thanked for critically reading and correcting this manuscript.References1. Lindsay GB, Rainey J. Psychosocial and pharmacologic explanations of nicotine's "gateway drug" function. 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A lesson in Intolerance

Professor Neil McKeganey (October 25) writes that "Perhaps what we need is a good deal more intolerance of all illegal drugs". We are perplexed at this opinion, which contradicts the evidence about solutions to drug problems. Be intolerant of the psychological, social and economic conditions that perpetuate drug problems, rather than of use and users.

Near-zero tolerance was tried between about 1980 and 1995, particularly in the US, while levels of illegal drug use rose to unprecedented levels. Fortunes are spent trying to diminish the supply of drugs, with minimal effect. The illegal drugs industry (one of the world's largest industries) will operate as long as there is demand for illegal drugs, passing on to the consumer the added costs of social and legal "intolerance". Increased expenditure on Customs and police activities would not be worth the cost. Furthermore, it serves the drugs industry's interests to remain illegal, because operating in an entirely unregulated fashion maximises profits.

Being intolerant of individual drug users might be an alternative. Is it possible to stigmatise and socially exclude people having problems with Class A drugs any further?

The Swedish intolerant approach has indeed suppressed the prevalence of drug use, but at the cost of inhumane stigmatisation of users. At one point, there were discussions about isolating all HIV-positive people on an island. Remember, Sweden takes a similarly intolerant view of alcohol. The consequences are lower rates of alcohol-related problems, but a high incidence of heavy binge drinking. An alternative model is the Netherlands, which has a lower prevalence of use than the UK despite more accommodation of drug users.

The hyped benefits of zero tolerance policing in the US are due to other factors, including a generation switching away from crack cocaine in disgust and alarm at what happened to their older brothers and sisters. Another example of the difficulties of zero tolerance is that that prisons cannot be made drug-free, only harsher and more unstable, as prisoners find ways to obtain drugs despite restrictions; this in a closed society. Making an open society drug-free may be impossible.

Some success has been achieved in Scotland with socially inclusive approaches. For example, by prescribing heroin users methadone and dispensing it on daily visits to community pharmacies. This approach was inspired in part by Neil McKeganey and Marina Barnard's classic book on heroin injectors. Other options include abstinence programmes for those who want them and tackling the conditions associated with some of the worst drug problems in society, namely poverty and poor life opportunities.

Most Scots have a cannabis user among their friends and family, whether they know it or not, as over 20% of younger adults have used in the previous year. Should we not also be intolerant of alcohol and tobacco, not mentioned in Neil McKeganey's article?

Not really: shuffling the classification of the drugs people get high on is beside the point. People can come to harm using any drug, or alcohol, or tobacco. They can also use most of these drugs, up to and including heroin and cocaine, without harm, as our own research has found. We need realistic mores, with formal and informal regulation of drug and alcohol use so that people come to the least harm possible. We should also tackle the social causes of problem drug-use. Intolerance on the other hand simply fosters a criminal and ethical free-for-all that relinquishes social control over who uses what, where, how, at what age and with whom.

Petition: INFORMED CONSENT, RIGHTS and OBLIGATIONS

The House of RepresentativesParliament BuildingsWellington,New Zealand

29th October, 2006

Petition of One:

On the matter ofINFORMED CONSENT, RIGHTS and OBLIGATIONS

When a society perpetuates negative, judgmental attitudes toward any group of people, especially with regard to their different values, beliefs and ways of life, it is being oppressive. This oppression results in people being stigmatised, marginalised and ostracised for their beliefs or actions. This oppression, in turn, gets internalised by the people who experience it.

I, Blair Anderson , resident of Christchurch East, on behalf of those for whom this oppression is real, damaging and life threatening, hereby petition the House of Representatives of the Parliament of New Zealand, to be heard before Health Select Committee in consideration of the matter of Medical Cannabis, and that receipt of this petition be acknowledged before said House in accordance with standing orders.

"Medicinal cannabis users have the right to make their own, personal fundamental health choices. This right is conferred under existing Human Rights and Bill of Rights legislation and is crucial to upholding an individuals right to INFORMED CONSENT"

New Zealand citizens should not have to choose between breaking the law to use any therapy of their choice, or be forced by circumstance into going without, thereby compromising well-being and quality of life.

The Minister of Health, under whom the warrant to investigate, search, arrest, seize and incarcerate on matters related to cannabis should have to provide evidence that proves that self administered cannabis therapy poses a greater risk to a person's health than the alternatives of either (a) doing nothing or (b) traditional [prevailing] medical practice.

Further it is petitioned that the HEALTH INTERVENTION resources currently diverted to Ministry of Police and Justice under said warrant, be re-allocated back to the Ministry of Health in accordance with New Zealand's signatory obligations to Ottawa Charter principles; for the furtherance of academic research and continuing good governance of those who are only trying to feel better, be it physically, emotionally, or psychologically, and also to protect and hold true, the rights of those who care for them.

The study is the first of its kind to analyze the effects of "stop and go" bus and truck diesel traffic versus highway traffic on infant respiratory health.

Published in the August issue of the Journal of Allergy and Clinical Immunology, results of the four-year study suggest that the type of traffic and distance from it-- not just traffic volume--are associated with infant wheezing.

Previous air pollution studies had not addressed these factors in infants.

"During the first year of life, an infant's lungs and immune system are still developing," said Patrick Ryan, lead author for the study in UC's Department of Environmental Health.

"Overexposure to harmful particulates at such a young age may play a role in the development of allergic conditions."

The researchers tracked the respiratory health of 622 infants living near three traffic conditions: highway traffic, "stop and go" traffic, and areas unexposed to major roads or bus routes.

A "stop and go" traffic area was defined as being within 100 meters (about 100 yards) of a bus or state route with a posted speed limit of 50 mph or less.

Research showed that infants living within 100 meters of "stop and go" traffic wheezed twice as often as those living within 400 meters (about 400 yards) of interstates, and more than three times as often as unexposed children.

Earlier research has shown that diesel exhaust particles (DEP), breathable particles able to absorb and transport proteins, aggravate rhinitis (hayfever) and asthma symptoms.

This year, U.S. Senator George Voinovich (R-OH) introduced the Diesel Emissions Reduction Act, an effort to improve air standards through diesel engine retrofits.

"Our findings reinforce the need to control diesel exhaust emissions," said epidemiologist Grace LeMasters, PhD, professor of environmental health and principal investigator of the study.

Alcohol in the top five most harmful drugs / NewScientist

The UK Science and Technology Select Committee commissioned an assessment of 20 legal and illegal stimulants to examine the actual social and physical harm they cause based on scientific evidence.

It reported in August. No one noticed! however,

......based on the track record to date, Kiwi's would in all probability get better outcomes if a range of prevelent 'deviant behavours' associated with Alcohol were displaced - and we adopted a harm reduction strategy that realistically enabled credible drug education, particularily amongst youth.

Taranaki parents wondering if their children are taking illegal drugs are about to get a helping hand from the Managers' Guild Trust.

The trust, formed by senior police, will distribute a journal early in the New Year to give parents the latest information about drugs available to children today.

[Police have a unfettered stakehold in advocating prohibitory practice, yet never account for the policy efficacy and have an even poorer record in delivery of education - DARE programme kids are more likely to come to harm with drug use than no DARE programme kids. Whenever I see "latest information", it is usually served up without references. Do the Police or its advocates understand the meaning of the word 'curriculum'? How about 'lesson plan' - followed by the word 'outcomes'.]

Campaign co-ordinator Jeremy Anderson said most parents liked to think other people's kids used drugs, rather than their own children.

[Jeremy, what planet are you on. If you want to reach parents dont start by telling them they are stupid, ignorant and dont care]

"This is not a good mindset, as peer pressure can be a big thing in any teenager's life."

[And Police/Manager's Guild is not "peer pressure" ? ]

"No one wants to imagine that their kid is going to be getting involved in that lifestyle, but no one is exempt," Mr Anderson said.

[An absolute function of prohibition... ]

P use was in every walk of life.

[A distorted representation of the prohibitors reality, 'P' has been used by a very small minority of people and in current use by even less. Alcohol misuse and abuse'in every walk of life' is however, accurate.]

New Zealand was slow reacting to the existence of methamphetamine type drugs.

[This is not true. NZ has been highly reactive classifying MDMA and precursors bypassing public consultation and scientific scrutiny. ]

"We have been caught out with P in this country, because it has come in the last five years and has made a heck of an impact with all of the people who deal and use drugs."

[Emerging prevelence of, and subsequently hazards related to meth is again a function of prohibition 'of other drugs' - see analysis Economics Professor Roumasset, Hawaii University]

Parents also saw taking drugs as a typical teenage thing that most kids tried, he said.

[Alcohol, Tobacco... Cannabis yes. And this is the very reason we shouldnt lie about relative harms to Parents or Teens. ]

"We can't let most kids try meth. The thing is highly addictive and highly expensive, so it turns into a problem rapidly."

[Meth turns into a problem rapidly because of criminalised prohibition practices. It couldnt be more available to younger folk than 'under prohibitions watch'. The medical literature shows nicotine to be more addictive than meth, and that treatment relative to Alcohol or Nicotine is for the majority of users, quite easy. ]

Users resorted to selling the drug or crime to pay for their habit.

[Prohibitions matrix of dysfunction at play]

Mr Anderson said he hoped the campaign would make parents aware of the danger signs to look for if their teenager was using drugs.

[While the writer shares similarily the view that the better informed we are, the better the outcomes should be. The crux, and differential is about 'whose views' produces the better outcomes. The Policy debate has to move beyond scare tactics and towards informed consent at every level, Police, Parents and Young folk. In this regard the Manager's Guild needs to be more circumspect and ask, what part of what we are doing now is failing us... could it be that doing more of the same and expecting a different result is misplaced endevour?]

"Prevention is the key. It is 10 times harder to get someone to quit once they have started."

[undeserving of a comment]

Open communication between parents and teenagers about drug use was the best way to keep them safe.

[In this, there is uniform agreement.. so why do we abrogate that responsibility to Police?]

"Don't just say, `look don't do drugs because they are illegal', but actually give them reasons why.

[And do aproved drugs that are legal? Whaaa !]

"The best thing a parent can do is be knowledgeable of where these drugs can take their kids and convince their kids not to go down that path," Mr Anderson said.

[How about a Reality Based drug policy predicated on Safety First.]

Legally available and popular party pills were seen as the gateway to harder, more serious drug abuse.

[There is NO EVIDENCE to support this gateway 'theory'. There is evidence that emergence of and thus availability of party pills is a function of (primarily cannabis) prohibition, and evidence that such availability (of cannabis and perty pills) is an effective harm reduction strategy. ]

"Our theory would be that kids who might not have used drugs are now realising these party pills are legal, so it kind of suggests they should try it."

[So there is an agenda here... ALL the drugs WE dont like are Bad in ANY amount]

Mr Anderson said once the novelty of party pills wore off, young people could be seduced by a better hit.

[No wonder the 1998 House of Representatives Health Select Committee Inquiry was at pains to point out, the 'double standards' are an impediment to credible drug education and harm prevention. In order to establish an effective education policy in respect of ALL drugs, we first have to resolve the tensions that underpin what's broken in what we do today. The Manager's Guild adds little too our understanding and in the view of the writer is contributing to continuing policy failure, accordingly it is [partially] responsible for the mayhem that ensues.]

Mind-altering drugs: does legal mean safe?

29 September 2006 / Exclusive from New Scientist Print Edition. Subscribe and get 4 free issues. by Gaia Vince

Lying back, exhaling: usually the last thing a person does before leaving this world. Only in this case it is the world that is leaving me.

A few minutes ago I smoked a pipe of Salvia divinorum, a powerful hallucinogenic herb that I bought openly and legally from a shop near my home. Of the £25 I handed over, more than £4 will find its way into government coffers in the form of sales tax. And salvia was just one of dozens of powerful but entirely legal psychoactive substances that I could have chosen.

All that was far from my mind as the salvia took me on a consciousness-expanding journey unlike any other I have ever experienced. My body felt disconnected from "me" and objects and people appeared cartoonish, surreal and marvellous. Then, as suddenly as it had began, it was over. The visions vanished and I was back in my bedroom. I spoke to my "sitter" - the friend who was watching over me, as recommended on the packaging - but my mouth was awkward and clumsy. When I attempted to stand my coordination was off. Within a couple of minutes, however, I was fine and clear-headed, though dripping with sweat. The whole experience had lasted less than 5 minutes.

My salvia trip was part of a journey into the world of "legal highs", a new generation of powerful mind-altering substances that are growing in popularity across the world (see Table). Accurate figures are hard to come by, as these substances are rarely monitored by drug-enforcement agencies. But the proliferation of online and high-street retailers suggest they are an increasingly lucrative business, and one company specialising in legal drugs recently reported an annual turnover of $16 million.

The reasons for their rising popularity are not hard to fathom. Not only are they legal and openly available in many countries, they work. Whether or not they are a good thing, however, is more difficult to decide. Supporters argue that legal highs are a bit of fun with a social conscience - a harm-reduction measure that allows people to experiment safely with psychoactive substances while separating drug use from criminality. Others say no one should be allowed to take such powerful drugs: the risks are too great. Some of the disagreement is down to the dearth of information about the short and long-term health effects of most of these substances, their potential for abuse and their addictiveness. But legal highs are also a battleground between those who see the use of mind-altering drugs as a human right and those who think it is plain wrong.

Faced with growing use and an information vacuum, governments are playing catch-up. Some, notably the US and Australia, are clamping down on each new substance as soon as they encounter it. Some are doing nothing. Others are commissioning research into the drugs and their effects before deciding what action to take.

And this is just the beginning. With hundreds of synthetic drugs on their way, not to mention traditional herbs that are being introduced to western consumers for the first time, some believe that cheap, easily available, legal highs could render the street drugs market redundant. So what do we know - and not know - about legal drugs?

Legal highs are nothing new. Paul Anand, manager of Shiva, the shop in Greenwich, London, where I bought my salvia, has been selling them for 15 years, starting with a stall at the Glastonbury festival. "Back then, I was selling guarana, damiana and wild lettuce," he says, "basically poor imitators of cannabis." There was a small market for the stuff, but among experienced drug users they were regarded as a joke, with few discernable effects.

That all changed with the arrival of new, reliable and effective substances, beginning in the UK at least with magic mushrooms. At the end of the 1990s, vendors started taking advantage of a legal loophole that permitted the sale of fresh mushrooms as long as they were not prepared in any way. Business boomed. In the year to April 2004 the number of shops selling magic mushrooms in England and Wales rose from a handful to over 400, according to the British Crime Survey. In the same period 260,000 people bought mushrooms - an increase of 40 per cent on the previous 12 months.

Image via WikipediaIn July 2005, the government closed the loophole, outlawing the sale of fresh mushrooms containing the hallucinogens psilocybin and psilocin, but by then it was too late. The demand for legal highs had been established, and high street and internet vendors rushed to fill the void with an assortment of alternatives. These include another type of magic mushroom, the fly agaric (Amanita muscaria), which does not contain psilocybin or psilocin but is packed with other hallucinogens including muscimol. Salvia is another. And then there is an astonishing assortment of psychoactive herbs, pills and potions designed to mimic the effect of pretty much every illegal drug going.

No dodgy dealers

Inside the shop, the cornucopia of offerings cannot be exaggerated. Vials and bottles crammed with herbal extracts, tinctures, seeds and powders jostle for attention with packets of "party pills". There are hallucinogens, relaxants, aphrodisiacs, trippy highs, "loved-up" pills and euphorics. All entirely legal, at least in the UK.

So why the sudden explosion? Anand says that his customers are attracted by the safety and quality of his products. "People are confident in what they're buying - that it's not cut with rat poison. They enjoy coming into the shop. They're not forced to meet a dodgy git in a UV-lit disco to buy an aspirin."

Vendors also make a selling point of legality. With drug testing increasingly routine at workplaces, 30 and 40-somethings are switching to highs that don't put them on the wrong side of the law, Anand says. And with legality comes, if not official approval, then at least an imprimatur of safety.

The majority of Anand's customers are aged between 20 and 30, he says. Most have tried street drugs and are now looking for something safer, more reliable, legal and affordable. And they're part of a growing movement: one leading vendor of legal highs, Stargate of Auckland, New Zealand, recently reported an annual turnover of NZ$24 million (approximately US$16 million).

Image via WikipediaAmong the most popular legal highs are "party pills" made from compounds called piperazines, which are chemically similar to Viagra but with an amphetamine-like action. Known by various brand names such as PEP and Bliss, their main active ingredient is BZP (benzylpiperazine) - the "Z" pronounced US-style to rhyme with the "B". Originally developed as a drug to treat parasites in livestock, piperazines have been sporadically used on the dance scene for many years but began to seriously take off about three years ago - though not in the US, where they have been strictly illegal since 2002. Anand started selling them in January 2006 and says that every month they grow more popular.

The BZP story started in the late 1990s, when the drug was "discovered" by New Zealand entrepreneur Matt Bowden. The former musician and recreational drug user became hooked on illegal amphetamines in the 1990s during an epidemic of methamphetamine - "crystal meth" - addiction that swept the country. He had already lost a family member to ecstasy when, in the mid-1990s, he witnessed a friend on meth commit a horrific suicide - disembowelling himself with a samurai sword - at a party.

Bowden became determined to kick the habit. His efforts to quit led him to experiment with legal alternatives and he sought out a professor of neuropharmacology to tutor him and work alongside him on the project.

"I said, let's find something which is like methamphetamine but non-addictive and has an extremely low risk of overdose or death," Bowden says. They searched through the scientific literature and came across a piperazine which occasionally cropped up as an ecstasy alternative called A2.

"We looked at a US study and found that one part of the molecule caused liver damage in rats, but the other part appeared to be perfectly safe. That part was BZP," he says.

In 2000, Bowden used the compound to break his addiction to methamphetamine and then began giving it out for free to friends. By 2002, companies had begun making and selling BZP. The move led Bowden to set up his own company, Stargate, to market safe, legal alternatives to street drugs.

Stargate now produces and sells a range of pills based on piperazine blends. BZP is often combined with another piperazine, TFMPP (trifluorophenylmethylpiperazine), which gives the pills a relaxing, euphoric effect that has been compared to ecstasy.

Both drugs activate the 5HT serotonin receptor in the brain - the same receptor targeted by amphetamines and MDMA - and cause the release of dopamine (Neuropsychopharmacology, vol 30, p 550). This is responsible for the "high" associated with the pills, though it can also lead to anxiety, overheating and dehydration. In one survey, only half of people who had used BZP said they would describe its effects as "good"; 16 per cent said it was "good early but bad later", 10 per cent "bad" and 14 per cent "neither good nor bad". My own experience of using BZP was mixed, with some enjoyable effects but also a bout of paranoia, insomnia and a bad hangover the next day.

Worldwide, Bowden sells a million pills a year and, all told, New Zealand's legal party pills industry is worth around NZ$50 million a year. As these figures suggest, a lot of New Zealanders take BZP. In June, researchers at Massey University in Auckland released the results of a survey of more than 2000 people, commissioned by the New Zealand government. "We expected that no more than 5 per cent of those questioned would have tried BZP, but we actually found that 20 per cent of people had tried the drug, and 1 in 7 of 15 to 45-year-olds had used BZP in the past year," says study leader Chris Wilkins.

Wilkins says that the highest usage was by those in their 20s, as he had expected, but he also discovered high levels of use by people in their 30s and 40s.

A separate survey of around 1000 people carried out in Hamilton, New Zealand's seventh-largest city, yielded similar figures. It found that 12 per cent of the city's total population, and 30 per cent of 14 to 25-year-olds, had taken BZP at some point (Emergency Medicine Australasia, vol 18, p 180).

The popularity of BZP, along with anecdotal reports of adverse reactions, withdrawal symptoms and psychotic episodes, has led some politicians and doctors to start campaigning for a ban. Bowden, however, argues that his products are "harmless fun" and actually reduce demand for street drugs and the damage they cause; the pills are even labelled as "drug-harm minimisation solutions". He and other vendors have an agreement to sell them only to adults and in outlets where alcohol is not available.

"If we accept that people have the right to experiment with their minds, just as they try paragliding or drag racing, then it is the responsibility of governments to ensure that they have access to well-designed drugs," Bowden says.

There is some evidence in support of Bowden's argument that BZP reduces the demand for street drugs. In the Hamilton survey, 44 per cent of the 15 to 45-year-olds who had tried BZP said they had stopped taking illegal drugs as a result. In 2005, the head of the New Plymouth Criminal Investigation Branch, Grant Coward, said that the use of ecstasy had dropped after BZP became available. It also appears that the relatively low price of BZP diverts people away from illegal drugs. An ecstasy pill in New Zealand costs up to NZ$80; the same amount will buy you up to 12 BZP tablets. "Most users said that they would rather take ecstasy than BZP because the effect is preferable and the hangover not as bad, but they're priced out of it," Wilkins says. What is not clear, however, is whether BZP acts as a gateway to illegal drugs among people who would otherwise never have taken them.

Wilkins also points out that the drug seems to have less abuse potential than amphetamines. "It gives you quite a bad hangover, so people tend to limit their usage of it," he says. Overall, however, Wilkins says it is too early to conclude that BZP reduces harm.

Health worries

Worries are also emerging about the health effects of the drug. According to emergency doctor Paul Gee from Christchurch Hospital, BZP-related admissions were almost unheard of two years ago but are now commonplace. Between April and September 2005, his team dealt with 80 users complaining of nausea, vomiting, anxiety and palpitations. Some had seizures; two cases were life-threatening (The New Zealand Medical Journal, vol 118, p U1784). And while there have been no deaths directly attributed to BZP, in 2001 a woman died in Zurich after taking it with MDMA.

One of the biggest worries is that, because BZP is advertised as a "safer alternative", it fosters the belief that it is completely harmless and encourages people to take more than the recommended dose (about 200 milligrams). In the Hamilton survey, around a third of 14 to 25-year-olds who had taken BZP said they did not read the instructions on the packaging. Nearly half took more than the recommended number of pills, and 66 per cent drank alcohol at the same time, which is not advisable as alcohol exacerbates the dehydrating effects of BZP.

The non-addictiveness and limited abuse potential of BZP have also been called into question with a study showing that rhesus monkeys will intravenously self-administer the drug at rates as high as they would for cocaine (Drug and Alcohol Dependence, vol 77, p 161). What's more, work due to be published in the journal Neurotoxicology and Teratology shows that adolescent rats given BZP grow up into anxious adults.

With the doubts about BZP growing, it is no surprise that governments are sitting up and taking notice. In 2002 the US temporarily placed the drug on its schedule 1 rating, the same category as MDMA and heroin, and confirmed this in 2004. BZP has recently been made illegal in Japan, Denmark, Greece, Sweden and, as of 1 September, Australia. In the UK, BZP remains legal but is on the agenda for discussion at the government's advisory council on the misuse of drugs meeting on 2 November, where a decision will be taken as to whether BZP needs to be monitored further.

New Zealand, however, has taken a different and arguably more enlightened approach. In 2001 Bowden approached the government to ask for its help in regulating the new industry. In response the government introduced a new class of drug called "non-traditional designer substances", also known as class D. This class is a repository for new and little-researched drugs, such as BZP, pending further information. Class D drugs are legal, though there are some restrictions on them; in BZP's case that means a ban on sales to under-18s and in places that sell alcohol.

The government also commissioned three studies into BZP. One, the Hamilton prevalence study, has already been published. The other two concern the drug's health effects and are due out in November; Wilkins expects both to be critical. The outcome of these studies will heavily influence the legal status of BZP in New Zealand.

Whatever the fate of BZP, party pills won't be the last legal high to occupy government time. Thanks to the efforts of Bowden and like-minded individuals, new psychoactive substances - both natural and synthetic - continue to enter the market.

The next craze is likely to be for a legal high called kratom. This extract of a tree native to south-east Asia has been dubbed the "herbal speedball" for its euphoric and energising properties. Kratom's main active ingredient, mitragynine, binds to the same opiate receptor (mu) as opium, heroin and cocaine. There are no documented overdoses or fatalities and proponents claim it is non-addictive, although last year a team from Josai International University in Togane, Japan, published evidence to the contrary (Life Sciences, vol 78, p 2). It is legal almost everywhere except Thailand and Australia. In high doses it is supposed to produce hallucinogenic effects. However, when I tried it - boiling the leaves to make a nauseating tea - it merely made me sick and sleepy.

According to a US National Drug Intelligence Center report published in 2005, kratom is cheap and widely available in the US and has "high abuse potential", though up to now there have been no moves to ban it. That is sure to change. Arguably, drugs such as kratom are legal not because they have official approval but by default: they have yet to become popular enough to attract the attention of lawmakers. Once that happens - as with magic mushrooms in the UK - governments are quick to clamp down.

Another high that appears to be on the brink of losing its legal status is salvia. Also known as diviner's sage, "magic mint" or "Sally D", Salvia divinorum is a white-and-blue-flowered sage plant that grows in the Oaxaca mountains in Mexico. It has been used for centuries by the Mazatec people in shamanistic rituals and in healing.

The first westerner to experience salvia's powerful hallucinogenic effects was anthropologist Brett Blosser, now of Humboldt State University in Arcata, California. In the late 1980s, he was invited to take part in a Mazatec shamanic ceremony in which the participants rolled up salvia leaves and chewed them. The effect was profoundly psychedelic, Blosser reported.

Inspired by Blosser's account, Daniel Siebert, an independent ethnobotanist from Los Angeles, distilled the plant's juices to produce white, needle-shaped crystals which he called salvinorum A. Just a tiny crumb of this on his tongue produced what he describes as the most awesome and frightening experience of his life. "Suddenly I lost all physical awareness. I felt as though I were completely conscious and yet I had no body. I wondered if I had died," he says.

In 2002, with recreational use of salvia on the rise in the US and elsewhere, Bryan Roth, director of the National Institute of Mental Health's psychoactive drug screening programme at Case Western Reserve University in Cleveland, Ohio, took an interest. He discovered that salvinorum A is highly selective for the recently discovered kappa opioid receptor in the brain (Proceedings of the National Academy of Sciences, vol 99, p 11934). Like the other two opioid receptors (mu and delta), kappa is involved in pain sensations. But, unlike the other two, chemicals bound to it can cause hallucinations.

It's still unclear why salvia produces hallucinations. "Some of the experiences people have on salvia may be similar to the psychosis that occurs in late-stage Alzheimer's," says Roth. "There is an increase in the number of kappa receptors in the brains of people with late-stage Alzheimer's."

All studies so far have shown salvia to be non-addictive. It also appears to have limited potential for abuse. "Most people taking drugs are not looking for an out-of-body experience, they want something gentle," says Harry Shapiro from UK drugs information charity DrugScope. "Salvia is so strong that people try it once and never take it again."

Playing with fire

Even so, possession of salvia has recently been made an offence in four US states - Louisiana, Missouri, Tennessee and Delaware - and a federal ban appears inevitable. Thomas Prisinzano of the University of Iowa in Iowa City, who is studying salvia to research new methods for treating substance abuse and pain, believes it is only a matter of time. "If LSD is schedule 1, then salvia will almost certainly be classed the same," he says.

Some researchers would welcome a ban on salvia and other new drugs. One of these is pharmacologist and substance misuse researcher Fabrizio Schifano of St George's Medical School in London. He says that the main problem with psychoactive substances - and hallucinogens in particular - is that they may incite psychosis. "How do you know if someone will have a sensitivity to the drug?" he says. "I am really worried by the prevalence of these drugs, and the fact that most users get their information from the internet. It is not peer-reviewed research, just people's opinions, and that is very dangerous."

Tim Kendall, deputy director of the Royal College of Psychiatrists research unit, says: "When you take salvia you are playing with fire. People can be very damaged in terms of their personal functioning. They frequently have flashbacks that intrude into their life, which can be almost like a post-traumatic stress problem after very bad experiences."

"My recommendation is that people should keep their minds clean," adds Roth.

Others believe that knee-jerk bans are the wrong approach. People have a natural drive to enter alternative states of mind, argues Richard Boire from the Center for Cognitive Liberty and Ethics in Davis, California. "The role of governments is to prevent harm to people and society from dangerous drug use. I think the government has lost sight of this and now thinks its role is to stop people from entering other mindsets."

For governments intent on pursuing prohibition at all costs, there is a sobering thought. For every banned psychoactive substance there are dozens more that remain legal. The legendary pharmacologist Alexander Shulgin has synthesised more than 230 novel designer drugs, and according to psychologist John Halpern, associate director of alcohol and drug abuse research at Harvard University, there are dozens of legal hallucinogenic herbs besides salvia that are already widely available on the internet and growing in popularity (Life Sciences, vol 78, p 519). What is more, there is clearly a demand for the stuff, and plenty of people like Bowden willing to supply it. Salvia, BZP and kratom may be on the way out, but others will take their place.

From issue 2571 of New Scientist magazine, 29 September 2006, page 40-45

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